Nuspojave lijekova supstrata metaboličkog enzima citokroma P450 CYP2C9 i transportnog P-glikoproteina

Macolić Šarinić, Viola (2012) Nuspojave lijekova supstrata metaboličkog enzima citokroma P450 CYP2C9 i transportnog P-glikoproteina. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Polymorphic metabolic enzymes and transport proteins can significantly modulate the pharmacokinetic parameters of medicinal products and therefore be a reason for the appearance of type A adverse reactions. The objective of this study was to test the adverse reactions to medicinal product substrates of the metabolic enzyme cytochrome P450 CYP2C9 and the transport P-glycoprotein (Pgp). Based on the retrospective and current collection of data on adverse drug reactions of the substrates CYP2C9 and Pgp, the role of polymorphism in the appearance of adverse reactions was estimated. All adverse reactions reported to the National database in the period 2005–2011 were analysed. Reports pertaining to drug substrates CYP2C9, CYP2C9 and Pgp, i.e. drugs with a substrate of the transport protein Pgp, were analysed if the drugs had a clearance via the said enzyme of greater than 10%, or if the clearance via CYP2C9 was between 5 and 10%, and there are drugs commonly used in combination with other drugs simultaneous, as is the case, for example, with acetylsalicylic acid. A group of 158 subjects with serious adverse reactions to drugs with a substrate of the metabolic enzyme CYP2C9 were selected from the adverse reactions database. The selected subjects experienced adverse reactions to drugs that were, for the most part, metabolised via the enzyme CYP2C9. These were primarily anticoagulants of the coumarin type, i.e. warfarin (n=30 subjects), nonsteroidal anti-inflammatory drugs ibuprofen, indomethacin, diclofenac, pyroxicam (n=32), anti-epileptics phenytoin, phenobarbitone and valproic acid (n=44), fluvastatin (n=46), and oral anti-diabetics glyburide and glibenclamide (n=6). In addition to the group of subjects with adverse reactions, a second group was selected of subjects without adverse reactions (n=155) and who corresponded to the adverse reaction group in terms of gender, diseases and concomitant therapy. Genotypisation of CYP2C9*2*3 and ABCB1 2677G>T/A, 3435C>T was conducted. An analysis of the National Adverse Reactions Database (kept by HALMED), and subsequent pharmacogenetic analysis established the following: • Adverse reactions to drugs (excluding vaccines) appear in women in more than 60% of cases, which has also been shown for drugs with the substrate CYP2C9, substrate CYP2C9 &Pgp, and substrate Pgp. • 60% of all reported adverse reactions in the database and adverse reactions to drug substrates were reported for adults (aged 17 to 69 years). • 8% of all drugs are based on the substrates CYP2C9, CYP2C9&Pgp or only the transport protein Pgp, while 69% of all reaction reports pertain to these drugs. • Adverse reactions from the entire group of drug substrates CYP2C9 have a statistically significant higher incidence of serious adverse reactions in comparison to other reports in the database (p<0.0004). • Adverse reactions from the drug group nonsteroidal anti-inflammatory drugs that have drug substrate CYP2C9 had a statistically significant higher incidence of serious adverse reactions in comparison to other reports in the database (p<0.006). • The higher the number of drug substrates CYP2C9 in simultaneous use, the greater the number of adverse reactions relating to gastrointestinal disorders, with a statistically significant high incidence of serious adverse reactions in comparison to other drugs in the database (p<0.006). • Of the substrates that are partially metabolised via CYP2C9 and which simultaneously have the substrate Pgp, the highest number of reports was received for diazepam and alprazolam which, in relation to other reports in the database, have a statistically significantly higher incidence of serious adverse reactions that is expected for other drugs, and that this increases with the number of drugs with the active compound diazepam taken simultaneously (p<0.002). • An analysis of the adverse reactions in terms of their severity also shows a statistically significant increase in the number of serious adverse reactions to warfarin (substrate CYP2C9 and PGP) in relation to other drugs in the database (p<0.00001). • In the case of cyclosporin (substrate Pgp) in combination with fluvastatin (CYP2C9 and Pgp), the largest number of reports were regarding adverse reactions from the group of skeleto-muscular disorders. The increased number of serious adverse reactions in this combination in comparison to other drugs in the database is statistically significant (p<0.01). • Amlodipin has the substrate Pgp and is a drug with the highest number of reported adverse reactions in the National database for tested substrates. In relation to the severity of reported adverse reactions for amlodipin, the adverse reactions reported for this drug in comparison to other drugs in the database are significantly lower in terms of the severity of adverse reactions (p<0.0001). • The group of subjects receiving therapy with drugs containing the substrates of the metabolic enzyme CYP2C9 and who developed one of the serious adverse reactions characteristic for these drugs, in comparison to the subjects without adverse reactions, were more often carriers of mutated alleles that determine reduced enzyme function, i.e. they belonged to the intermediate or slow metabolic phenotype that represents a predisposition for accumulation of the drug in the body and the development of adverse reactions. • In the homogeneously separated groups of subjects receiving therapy of warfarin, nonsteroidal anti-inflammatory drugs, and anti-epileptics phenytoin, fenobarbiton or valproic acid, and who developed one of the serious adverse reactions, again these subjects were often intermediate and slow metabolic phenotypes in comparison to the group without adverse reactions receiving the same therapy. • From the study, it can be concluded that the polymorphism of the metabolic enzymes CYP2C9*2 and *3 could be considered a pharmacogenetic predisposition for the appearance of serious adverse reactions to drugs that are primarily metabolised via the enzyme CYP2C9. That means that these adverse reactions could be predicted with the genotypisation of CYP2C9 prior to taking the drugs. The therapy for these patients should be adapted to the genotype, and the dose reduced according to the algorithms and recommendations. This is especially important for drugs with a narrow therapeutic index, such as warfarin and phenytoin. • The study did not prove that polymorphisms of Pgp (ABCB1) could serve as a pharmacogenetic marker. Though in some variations of the gene ABCB1 a difference in the distribution of alleles and genotypes was observed between groups of subjects with adverse reactions in comparison to those without adverse reactions, the difference was not statistically significant, with the exception of warfarin and fluvastatin; however, this indicates that it would be worthwhile expanding the research to larger homogenous groups of subjects. • The National Pharmacovigilance Centre could be a good starting point for pharmacogenetic studies, as data from different sources could be brought together in the assessment of causal relationships between medicine use and adverse reasons. Also, as the regulatory body changes the medicinal product documentation, i.e. Summary of Product Characteristics and Patient Instructions for Use, the Centre could therefore contribute to reducing the appearance of serious adverse reactions and enable the safest possible use of medicinal products and doses in long-term use.

Abstract in Croatian

Polimorfni metabolički enzimi i transportni proteini mogu značajno modulirati farmakokinetske parametre lijekova i biti razlogom nastanku nuspojava tipa A. Stoga je cilj ovog istraživanja bio ispitati nuspojave lijekova supstrata metaboličkog enzima citokroma P450 CYP2C9 i transportnog P-glikoproteina (Pgp). Na temelju retrospektivno i prospektivno sakupljenih podataka o nuspojavama lijekova supstrata CYP2C9 i Pgp procijenili smo i ulogu polimorfizama u nastanku ozbiljnih nuspojava. Iz Nacionalne baze analizirane su sve prijave nuspojava na lijekove iz razdoblja 2005. – 2011. godine. Prijave koje su sadržavale lijekove supstrate CYP2C9, CYP2C9 i Pgp, odnosno lijekove koji su supstrati transportnog proteina Pgp uzete su za analizu ako su lijekovi čiji je klirens preko navedenog enzima veći od 10%, odnosno u razmatranje su uzeti i oni čiji je klirens putem CYP2C9 između 5 i 10%, a radi se o lijekovima koji se često koriste u kombinaciji s drugim lijekovima istovremeno kao što je to primjer kod acetilsalicilne kiseline. Iz baze obrađenih prijava nuspojava odabrana je skupina od 158 ispitanika s ozbiljnim nuspojavama na lijekove supstrate metaboličkog enzima CYP2C9. Birani su bolesnici koji su razvili nuspojave na lijekove koji se najvećim dijelom metaboliziraju putem enzima CYP2C9. To su prvenstveno bili antikoagulansi kumarinskog tipa, u našoj populaciji varfarin (n=30 ispitanika), nesteroidni protuupalni lijekovi ibuprofen, indometacin, diklofenak, piroksikam (n=32), antiepileptici fenitoin, fenobarbiton i valproična kiselina (n=44), fluvastatin (n=46), te oralni antidijabetici gliburid i glibenklamid (n=6). Skupini ispitanika s nuspojavama pridružena je skupina ispitanika bez nuspojava (n=155), koja je prema dobi spolu, bolestima i konkomitantnoj terapiji odgovarala skupini s nuspojavama. Provedena je genotipizacija CYP2C9*2*3 te ABCB1 2677G>T/A, 3435C>T. Analizom Nacionalne baze za nuspojave lijekova (HALMED), te provedbom farmakogenetičkih analiza utvrđeno je: • da se nuspojave na lijekove (bez cjepiva) u više od 60% pojavljuju u žena, što je također pokazano za lijekove supstrate CYP2C9, supstrate CYP2C9 &Pgp, te supstrate Pgp • 60% svih prijavljenih nuspojava u bazi i nuspojava za lijekove supstrate prijavljene su za odrasle osobe (od 17 do 69 godina starosti) • 8% lijekova u bazi su supstrati CYP2C9, CYP2C9&Pgp ili samo transportnog proteina Pgp, a na njih se odnosi 69% svih prijava • Nuspojave iz cijele grupe lijekova supstrata CYP2C9 imaju statistički značajno više ozbiljnih nuspojava u odnosu na ostale prijave u bazi (p<0,0004) • Nuspojave iz grupe lijekova nesteroidnih protuupalnih lijekova koji spadaju u lijekove supstrata CYP2C9 imaju statistički značajno više ozbiljnih nuspojava u odnosu na ostale prijave u bazi (p<0,006). • Što je veći broj lijekova supstrata CYP2C9 u istovremenoj primjeni veći je broj nuspojava poremećaja probavnog trakta te ih je značajno više ozbiljnih, što je i statistički značajno u odnosu na ostale lijekove u bazi (p<0,006) • Od supstrata koji se djelomično metaboliziraju putem CYP2C9 a istovremeno su supstrat Pgp najveći broj prijava zabilježen je za diazepam i alprazolam koji u odnosu na ostale prijave u bazi imaju statistički značajno veći broj ozbiljnih nuspojava nego što se očekuje prema ostalim lijekovima, te on raste s brojem istovremeno uzetih lijekova s aktivnom supstancom diazepama (p<0,002). • Analizom nuspojava prema ozbiljnosti također se nalazi statistički značajno veći broj ozbiljnih nuspojava za varfarin (supstrat CYP2C9 i PGP) u odnosu na ostale lijekove u čitavoj bazi (p<0.00001). • U slučaju ciklosporina (supstrat Pgp) u kombinaciji s fluvastatinom (CYP2C9 i Pgp), u najvećem broju prijava se radilo o nuspojavama iz SOC-a „Poremećaji mišićno-koštanog sustava“. Povećani broj ozbiljnih nuspojava u ovaj kombinaciji u odnosu na ostale lijekove u bazi je i statitički značajan (p<0,01). • Amlodipin kao supstrat Pgp je lijek s pojedinačno najviše prijavljenih nuspojava u Nacionalnoj bazi za ispitane supstrate. U odnosu na ozbiljnost prijavljenih nuspojava za amlodipin nuspojave prijavljene za ovaj lijek u odnosu na ostale lijekove u bazi značajno imaju manje ozbiljnih nuspojava (p<0,0001). • Skupina ispitanika na terapiji lijekovima supstratima metaboličkog enzima CYP2C9 koja je razvila neku od ozbiljnih nuspojava karakterističnih za te lijekove u odnosu na ispitanike bez nuspojava bila je češće nosioc mutiranih alela koji određuju smanjenu funkciju enzima, tj. pripadali su intermedijarnom ili sporom metaboličkom fenotipu koji predstavlja predispoziciju za nagomilavanje lijeka u organizmu i razvoj nuspojava. • U homogenim odvojenim skupinama ispitanika na terapiji varfarinom, nesteroidnim protuupalnim lijekovima, te antiepilepticima fenitoinom, fenobarbitonom ili valproičnom kiselinom koji su razvili neku od ozbiljnih nuspojava također je češće bio zastupljen intermedijarni i spori metabolički fenotip u odnosu na skupinu na istoj terapiji bez nuspojava. • Iz provedenog istraživanja možemo zaključiti da se polimorfizmi metaboličkog enzima CYP2C9*2 i*3 mogu smatrati farmakogenetičkom predispozicijom za nastanak ozbiljnih nuspojava lijekova koji se najvećim dijelom metaboliziraju putem enzima CYP2C9. To znači da se dio ovih nuspojava mogao predvidjeti da je prije uzimanja lijeka provedena genotipizacija CYP2C9. Tim bolesnicima treba prema genotipu prilagoditi, smanjiti dozu prema algoritmima i preporukama. To je posebno važno za lijekove s uskim terapijskim rasponom kao što su varfarin i fenitoin. • U provedenom istraživanju nismo dokazali da polimorfizmi Pgp (ABCB1) mogu poslužiti kao farmakogenetički biljeg. Premda je za neke varijante gena ABCB1 uočena razlika u distribuciji alela i genotipova između skupina ispitanika s nuspojavama i skupina koji nisu razvili nuspojavu, ta razlika nije dosegla statističku značajnost, osim u slučaju varfarina i fluvastatina, ali upućuje da bi bilo vrijedno istraživanje proširiti na većim homogenim skupinama ispitanika. • Nacionalni centri za farmakovigilanciju mogu biti dobro polazište za farmakogenetičke studije, jer se mogu udružiti podaci iz različitih izvora u procjeni uzročnih veza između uzimanja lijeka i nuspojave, te kao regulatorno tijelo mijenjati dokumenatciju o lijeku – Sažetak opisa svojstava lijeka i prateću Uputu za pacijenta i time doprinijeti smanjenju pojavnosti ozbiljnih nuspojava lijekova i omogućiti najsigurniju primjenu lijeka i doze u dugotrajnoj primjeni.

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